Randomized Controlled Study Using Ropivacaine with Intravenous Adjuvants in Spinal Anaesthesia In Lower Limb Surgeries.

BACKGROUND: In recent years, several adjuvants have been used to prolong the duration of the subarachnoid block. These adjuvants have either been used via intrathecal route or intravenous (i.v.) route. Dexmedetomidine and clonidine have been used as adjuvants to local anesthetic drugs by intrathecal, epidural, caudal, and i.v. routes and for peripheral nerve blocks. In this study, we endeavored at finding the efficacy of dexmedetomidine and clonidine in improving the analgesia quality and duration of the subarachnoid block. SETTING AND
DESIGN: A prospective, double-blind, randomized control trial comprising 70 subjects posted for elective lower limb surgeries.
MATERIALS AND METHODS: Seventy patients were selected at random and were allocated to two groups (Group C and Group D) of 35 each. In Group C, the patients received isobaric ropivacaine with clonidine 1.0 μg.kg-1 intravenously. In Group D, the patients received isobaric ropivacaine with dexmedetomidine 0.5 μg.kg-1 intravenously. Perioperatively, heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and oxygen saturation were recorded and documented every 5 min till the end of surgery. Time of onset, level of sensory blockade, and duration of sensory blockade were recorded. Motor block was assessed using modified Bromage scale. Data validation and analysis were carried out by SPSS version 16. A P < 0.05 was considered statistically significant.
RESULTS: Time of onset of sensory block in Dexmedetomidine group and Clonidine group was 2.70 ± 1.25 minutes and 3.50 ± 1.23 minutes respectively (P = 0.021). Time of onset of motor block in Dexmedetomidine group and Clonidine group was 3.55 ± 1.60 minutes and 4.30 ± 1.45 minutes respectively (P = 0.034). Time for 2 segment regressions of sensory block in Dexmedetomidine group and Clonidine group was 140.30 ± 12.32 minutes and 125.65±14.33minutes respectively (P = 0.047). Time of regressions of motor blockade to Bromage Scale 1 in Dexmedetomidine group and Clonidine group was 148.65 ± 15.23 minutes and 129.70 ± 19.35 minutes respectively (P = 0.032).
CONCLUSION: The use of i.v. dexmedetomidine perioperatively prolongs the duration of sensory and motor block significantly when compared to i.v. clonidine. Copyright:

INTRODUCTION

Many techniques and drug regimens with partial or greater success have been tried from time to time to eliminate the anxiety component and to prolong the postoperative analgesia during regional anesthesia. Although beneficial in acute and chronic pain management, the use of local anesthetics is limited by its duration of action and the dose-dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anesthetics for its synergistic effect by prolonging the duration of sensory–motor block and limiting the cumulative dose requirement of local anesthetics. The α2 adrenergic agonists have both analgesic and sedative properties when used as an adjuvant to regional anesthesia. They potentiate the effect of local anesthetics and prolong the duration of both motor and sensory spinal blockade and postoperative analgesia.[1]

An adjuvant is a pharmacological agent which is added to a drug to increase or aid its effect. Opioids, first and foremost, have attained an integral role as a spinal anesthetic adjuvant. However, research has supported a number of nonopioid adjuvants which prolong the duration of spinal anesthesia.[23] Recently, α2 adrenergic agonists have been used as adjuvants to local anesthetic agents because of their sedative, analgesic, and hemodynamic stabilizing effect. They have been found to prolong the duration of spinal block following intrathecal administration.[4]

If the duration of surgery prolongs, it has to be converted into general anesthesia in which the patient is subjected to the administration of intravenous (i.v.) drugs and inhalation agents along with its side effects and financial burden to the patient. Hence, to improve the efficacy of the spinal anesthesia, adjuvants from different pharmacological classes of drugs are used to enhance the action of the drug, to prolong anesthesia, to lower its dose requirements, and to reduce dose-dependent side effects.[567]

Dexmedetomidine is a selective α2 adrenergic agonist. It has α2/α1 selectivity ratio 8–10 times higher than that of clonidine. Analgesic and sedative properties were found when intrathecal, epidural, or i.v. dexmedetomidine was used as an adjuvant in previous studies. There are plenty of studies that have compared the dose equivalence of these two drugs; however, various studies have established that the dose of clonidine is 1.5–2 times higher than the dose of dexmedetomidine.[8910]

Clonidine is a partial α2 adrenergic agonist. It causes decrease in the sympathetic tone and enhances the vagal tone. Stimulation of the α2 receptors in the vasomotor centers of medulla oblongata produces this effect. Clonidine is also used in the treatment of hypertension. Clonidine when added to local anesthetic for spinal and regional blocks has been shown to result in prolongation of the sensory blockade and reduction in the amount of concentration of local anesthetic required to produce postoperative analgesia.[11121314]

In this context, present research intends to compare the efficacy of i.v. dexmedetomidine and i.v. clonidine as an adjuvant to ropivacaine-induced spinal anesthesia.

Aim of the study

To compare the efficacy of i.v. administration of dexmedetomidine and i.v. administration of clonidine as an adjuvant to ropivacaine-induced spinal anesthesia.

MATERIALS AND METHODS

The present study was carried out as a prospective, randomized, double-blinded controlled method. Written and informed consent was taken from 70 adult patients of age group of 20–60 years of American Society of Anesthesiologist's (ASA) Physical Status Classification I and II.[15] These patients were posted for elective lower limb surgeries under spinal anesthesia. Exclusion criteria were as follows: patients with infection at the site of spinal anesthesia, patients with uncontrolled hypertension and diabetes, patients with any neurological or psychiatric diseases, and patients with coagulation disorders. Routine and detailed preanesthetic evaluations of all the subjects were carried out and were randomly allocated into two groups as and when the cases were posted for elective lower limb surgery.

The patients were nil by mouth 8 h before the proposed procedure. Patients received tablet ranitidine 150 mg at night before surgery at 10 pm and at 5.30 am with a sip of water as premedication. i.v. line was secured with an 18G cannula. All the patients were preloaded with Ringer's lactate 10 mL.kg − 1, 15 min before the surgery. Standard monitoring namely oxygen saturation (SpO2) heart rate (HR), noninvasive blood pressure, and electrocardiogram were attached, and baseline hemodynamic values were recorded. Aseptic precautions were followed while administering spinal anesthesia. With 25G Quincke spinal needle, subarachnoid block was performed at L3–L4 interspace in the midline with 0.5% isobaric ropivacaine (Neon Pharmaceuticals, India).

Group C received 3 mL of 0.5% isobaric ropivacaine with 1.0 μg.kg −1 of clonidine intravenously. Group D received 3 mL of 0.5% isobaric ropivacaine with 0.5 μg.kg −1 of dexmedetomidine intravenously. The adjuvants were administered via a syringe pump. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), SpO2, and HR were recorded preoperatively and after performing the subarachnoid block, every 5 min till the end of the procedure. Time of onset of anesthesia was recorded. Sensory blockade was assessed and recorded using pin prick in the mid-clavicular line on both sides. Modified Bromage scale was used to assess and record motor blockade. In the postanesthesia recovery room, the parameters were recorded every 15 min.

Statistical analysis

Simple randomization method was employed. Duration of the study was approximately 6 months. A pilot study was conducted, and the sample size was arrived with the help of previous studies keeping in mind the case load at our institution, the aforementioned number was arrived at.

The following formula was employed to arrive at the sample size.

where Z = Z value (e.g., 1.96 for 95% confidence level), P = percentage picking a choice, expressed as decimal, (0.5 used for sample size needed), c = confidence interval, expressed as decimal (e.g., 0.04 = ±4).

The baseline, intraoperative, and postoperative hemodynamic changes at various time intervals were compared between the study groups using Chi-square test and unpaired t- test. Data validation and analysis were carried out by SPSS version 11.0 (Statistical Package and Service Solutions, SPSS Statistics, IBM). A P < 0.05 was considered statistically significant.

RESULTS

In the Dexmedetomidine group, there were 4 patients in age group 20 – 25 years, 7 patients in 26 – 30 years, 7 patients in 31 – 35 years, 4 patients in 36 – 40 years, 9 patients in 41 – 45 years and 4 patients in 46 – 50 years. In Clonidine group, there were 5 patients in age group 20 – 25 years, 6 patients in 26 – 30 years, 6 patients in 31 – 35 years, 5 patients in 36 – 40 years, 8 patients in 41 – 45 years and 5 patients in 46 – 50 years [Table 1]. There were 18 males and 18 females in Dexmedetomidine group and 18 males and 16 females in Clonidine group [Table 2]. In our study, 27 subjects in Dexmedetomidine group and 29 subjects in Clonidine group were in ASA grade 1. Similarly 8 subjects in Dexmedetomidine group and 6 subjects in Clonidine group were in ASA grade 2.

Table 1

Age profile

Age group (years)	Dexmedetomidine group (%)	Clonidine group (%)	P
20-25	4 (05.71)	3 (08.57)	>0.05
26-30	7 (25.71)	8 (22.86)	>0.05
31-35	6 (22.86)	5 (14.29)	>0.05
36-40	5 (11.43)	6 (17.14)	>0.05
41-45	10 (20.00)	9 (25.71)	>0.05
46-50	3 (14.29)	4 (11.43)	>0.05
Total	35	35

The subjects in both the groups were demographically similar

Table 2

Gender profile

Gender	Dexmedetomidine group	Clonidine group	P
Male	18	19	>0.05
Female	17	16	>0.05

Time of onset of sensory block in Dexmedetomidine group and Clonidine group was 2.70 ± 1.25 minutes and 3.50 ± 1.23 minutes respectively (P = 0.021). Time of onset of motor block in Dexmedetomidine group and Clonidine group was 3.55 ± 1.60 minutes and 4.30±1.45 minutes respectively (P = 0.034) [Table 3]. Time for 2 segment regressions of sensory block in Dexmedetomidine group and Clonidine group was 140.30 ± 12.32 minutes and 125.65 ± 14.33minutes respectively (P = 0.047). Time of regressions of motor blockade to Bromage Scale 1 in Dexmedetomidine group and Clonidine group was 148.65 ± 15.23 minutes and 129.70 ± 19.35 minutes respectively (P = 0.032) [Table 4].

Table 3

Time of onset of blockade

Variable (min)	Dexmedetomidine group	Clonidine group	P
Time of onset of sensory block	2.93±1.34	3.46±1.13	>0.05
Time of onset of motor block	3.67±1.51	4.17±1.62	>0.05

Time of onset of sensory block in the dexmedetomidine group and the clonidine group was 2.93±1.34 and 3.46±1.13 min, respectively (P=0.021). Time of onset of motor block in the dexmedetomidine group and the clonidine group was 3.67±1.51 and 4.17±1.62 min, respectively (P=0.034)

Table 4

Time for regression of sensory and motor block

Variable	Dexmedetomidine group	Clonidine group	P
2 segment regression (min)	136.31±12.54	128.67±14.53	>0.05
Regression to Bromage Grade 1 (min)	145.76±15.37	158.76±19.65	>0.05

Time for 2 segment regressions of sensory block in the dexmedetomidine group and the clonidine group was 136.31±12.54 and 128.67±14.53 min, respectively (P=0.047). Time of regressions of motor blockade to Bromage scale 1 in the dexmedetomidine group and the clonidine group was 145.76±15.37 and 148.76±19.65 min, respectively (P=0.032)

In the Dexmedetomidine group, duration of analgesia was 195.70 ± 21.75 minutes whereas in Clonidine group it was 160.42 ± 34.30 minutes (P < 0.001). In the Dexmedetomidine group, the time for first rescue analgesic requirement was 210.64 ± 24.25 minutes whereas in the Clonidine group it was 166.25±36.45 minutes (P < 0.001) [Table 5]. In Dexmedetomidine group, bradycardia was observed in 6 patients, hypotension was observed in 5 patients, Ramsey Sedation score of more than 3 was observed in 6 patients, nausea and vomiting was complained by 2 patients. In the Clonidine group, bradycardia was observed in 2 patients, hypotension was observed in 2 patients, Ramsey Sedation score of more than 3 was seen in 4 patients and 1 patient complained of nausea and vomiting. These were managed as per the study protocol. These differences were found to be statistically significant [Table 6].

Table 5

Rescue analgesia

Variable	Dexmedetomidine group	Clonidine group	P
Rescue analgesia (min)	226.64±24.71	186.73±37.32	0.001

In the dexmedetomidine group, the time for first rescue analgesic requirement was 226.64±25.71 min, whereas in the clonidine group, it was 186.73±37.32 min (P<0.001)

Table 6

Adverse events

Adverse events	Dexmedetomidine group	Clonidine group	P
Bradycardia	6	2	0.08
Hypotension	5	2	0.09
Nausea/vomiting	6	4	0.52
Sedation score >3	2	1	0.56

In the dexmedetomidine group, bradycardia was observed in 6 patients, hypotension was observed in 5 patients, Ramsay sedation score of >3 was observed in 6 patients, ad nausea and vomiting was complained by 2 patients. In the clonidine group, bradycardia was observed in 2 patients, hypotension was observed in 2 patients, Ramsay sedation score of >3 was seen in 4 patients, and 1 patient complained of nausea and vomiting. These were managed as per the study protocol. These differences were found to be statistically significant

In the Dexmedetomidine group, the intra operative Ramsey Sedation score was 2.30 ± 0.65 minutes whereas in the Clonidine group it was 1.40 ± 0.51 minutes (P < 0.05) [Graph 1]. The hemodynamic parameters were compared. The Heart Rate (P < 0.05) [Graph 2], Systolic Blood Pressure (P < 0.05) [Graph 3], Diastolic Blood Pressure (P < 0.05) [Graph 4] and the Mean Arterial Pressure (P < 0.05) [Graph 5] were found to be statistically significant.

Graph 1

Ramsay sedation score

Graph 2

Heart rate

Graph 3

Systolic blood pressure

Graph 4

Diastolic blood pressure

Graph 5

Mean arterial pressure

DISCUSSION

Spinal anesthesia is a type of regional anesthesia technique where local anesthetic solution is injected into the subarachnoid space. It is widely preferred in urologic, cesarean, and lower limb procedures. Sedation is administered to allay the patient's anxiety of the surgical procedure. Sedation is administered via the i.v. route. Dexmedetomidine, an imidazole compound, is the pharmacologically active dextroisomer of medetomidine that displays specific and selective α2 adrenoceptor agonism. Activation of the receptors in the brain and spinal cord inhibits neuronal firing and results in sympatholytic effect, causing hypotension, bradycardia, and sedation.[16]

In our study, it is clearly evident that both dexmedetomidine and clonidine prolong the duration of spinal anesthesia. Primary outcome of this study is that dexmedetomidine is more preferred due to its longer duration of adjuvant action. Dexmedetomidine is known to cause bradycardia, which we found in our study and was clinically treated without any untoward incident.

In a study done by PDW Fettes et al, plain and hyperbaric solutions of ropivacaine for spinal anaesthesia were compared and it was shown that isobaric ropivacaine provided adequate analgesia for lower limb procedures.[17]

In a study done by Balwinder Kaur Rekhi et al, it was found that intravenous dexmedetomidine prolonged the effect of ropivacaine (3 mg).[18]

In a study done by J Chinnappa et al., perineural dexmedetomidine with ropivacaine provided prolonged postoperative analgesia, hastened the onset of sensory and motor block and prolonged the duration of the supraclavicular brachial plexus block.[19]

In a study conducted by Agarwal et al., it was observed that intravenous dexmedetomidine produces a better clinical profile compared to clonidine.[20]

Motor and sensory block prolongation with the use of α2 agonist, dexmedetomidine and clonidine, occurs as a result of differential block of Aα and C fibers. Dexmedetomidine does not cause significant respiratory depression despite providing good sedation proving its high safety margin.[212223]

CONCLUSION

Premedication with i.v. dexmedetomidine significantly prolongs the duration of sensory and motor block and provides intraoperative sedation and postoperative analgesia. Both dexmedetomidine and clonidine causes hypotension and significant bradycardia which are transient and easily treatable. Dexmedetomidine provides a longer duration of sensory block, motor block, sedation, and postoperative analgesia than clonidine without significantly increasing the incidence of adverse effects.

Limitations of the study

On comparing with other study models, we had hoped for a higher sample size. This was limited by the low number of cases undergoing surgery at our institution within the given time frame. We hope to overcome this in the future studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.